The present invention relates generally to methods for improving the transport and delivery of pharmaceutical agents across membranes. More particularly, the invention relates to methods for enhancing the transport and delivery of pharmaceutical agents through the addition of one or more chemical modifiers to the pharmaceutical agent.
The therapeutic efficacy of pharmaceutical or therapeutic agents relies on the delivery of adequate doses of a pharmaceutical agent to the site of action. Many modes of delivery have been developed, including, for example, enteral (oral), parenteral (intramuscular, intravenous, subcutaneous), and topical administration. In most instances the administration system is chosen for reliable dosage delivery and convenience.
Typically, parenteral administration is the most reliable means of delivering a pharmaceutical to a patient. See, Goodman et al., Goodman and Gilman's Pharmacological Basis of Therapeutics, Pergamon Press, Elmsford, N.Y. (1990) and Pratt et al. Principles of Drug Action: The Basis of Pharmacology, Churchill Livingstone, New York, N.Y. (1990). Each parenteral mechanism insures that a prescribed dosage of the pharmaceutical agent is inserted into the fluid compartment of the body where it can be transported. The disadvantage of these modes of delivery is that they require an invasive procedure. The invasive nature of administration is inconvenient, painful and subject to infectious contamination.
Enteral and topical administration are more convenient, generally non-painful, and do not predispose to infection; however, both are limited. The gastrointestinal and dermal surfaces present formidable barriers to transport and therefore, some pharmaceutical agents are not absorbed across these surfaces. Another drawback to patient directed modes of administration (enteral, topical and subcutaneous) is compliance. Pharmaceutical agents that have a short half-life require multiple daily doses. As the number of doses increases, patient compliance and therapeutic efficacy decrease. Simplified and/or less frequent administration schedules can aid in optimizing patient compliance. Wilson et al. (1991) Harrison's Principles of Internal Medicine, 12th Ed., McGraw-Hill, Inc., New York, N.Y.
The skin is an efficient barrier to the penetration of water soluble substances, and the rate of transdermal pharmaceutical agent absorption is primarily determined by the agent's lipid solubility, water solubility, and polarity. Highly polar or water soluble pharmaceutical agents are effectively blocked by the skin. Even very lipophilic pharmaceutical agents penetrate the dermis very slowly compared with the rate of penetration across cell membranes. See Pratt et al. supra.
Efforts to develop more effective and convenient modes of pharmaceutical administration have led to the development of transdermal delivery systems. Many current transdermal pharmaceutical agent delivery systems rely upon pharmaceutical agents that are absorbed when admixed with inert carriers. See Cooper et al. (1987) "Penetration Enhancers", in Transdermal Delivery of Drugs, Vol. II, Kyodonieus et al., Eds., CRC Press, Boca Raton, Fla. Few pharmaceutical agents fit this profile and those which do are not always predictably absorbed. Various forms of chemical enhancers, such as those enhancing lipophilicity, have been developed to improve transdermal transport when physically mixed with certain therapeutic agents and provide more predictable absorption. See for example, U.S. Pat. Nos. 4,645,502; 4,788,062; 4,816,258; 4,900,555; 3,472,931; 4,006,218; and 5,053,227. Carriers have also been coupled to pharmaceutical agents to enhance intracellular transport. See Ames et al. (1973) Proc. Natl. Acad. Sci. USA, 70:456-458 and (1988) Proc. Int. Symp. Cont. Rel. Bioact. Mater., 15:142.
Electric gradients also have been used to enhance transdermal pharmaceutical agent delivery. See Chien et al. (1989) Journal of Pharmaceutical Sciences, 78(5):353-354 and Banga et al. (1988) J. Controlled Release, 7:1-14. This technique, known as iontophoresis, uses an electric field to enhance the rate of delivery of ionized pharmaceutical agents through the skin. Typically, devices are used which hold a pharmaceutical agent in a reservoir near the skin, generate an electric field surrounding the pharmaceutical agent-dermal interface, and drive the agent through the skin.
For iontophoretic delivery, the drug molecules must be in an ionized state with either a positive or negative charge. Nonionic drugs may also be delivered iontophoretically provided that a charge can be induced on them, for example, by adsorption of drug onto an ionic carrier or entrapment in an ionic micelle. See Banga (1988) J. Controlled Release, 7:1-24.
The rate of drug delivery in iontophoresis is directly proportional to the system current; the higher the current, the greater the driving force and pharmaceutical agent delivery. Ionic strength also affects the iontophoretic drug delivery rate. See Banga supra. Ionic strength is related to the concentration of various ions present in the solution of the pharmaceutical agent in the reservoir. Other factors that may affect the delivery rate include pH, concentration, extraneous ions, conductivity, and electronic factors.